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How can we "stimulate" mTOR?

Murph

:)
Messages
1,799
@Murph Do you think reducing AMPK in the hypothalamus would be helpful?
Would increasing AMPK in adipose tissue be harmful?
What do you think about trying PEA?

Apparently PPAR-alpha can be both activated and suppressed by mTORC1 depending on the cell type, and PPAR-gamma is purely activated by mTORC1. If mTORC1 is underactive in PWME, than perhaps PPAR-gamma is low.
Also, AMPK suppresses both PPAR alpha and gamma (Reference)

@nandixon What do you think about PEA? In summary, it inhibits AMPK in the hypothalamus, activates AMPK in fat tissue, from what I can tell disinhibits mTOR through disrupting the PERK-eIF2α pathway, and activates PPAR alpha and gamma.
I really totally honestly have no idea. I'd probably steer away from it without getting advice from someone far more knowledgeable!! how was the ketamine anyway??
 
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eljefe19

Senior Member
Messages
483
@Murph Ketamine was nice. I enjoyed both some palliative relief of ME/CFS symptoms (pain and fatigue) but I also got some great mood boosting effects as well. Also music is enhanced on it. Are you considering a trial?

More info on mTOR/AMPK;

http://www.nature.com/nm/journal/v16/n9/full/nm.2207.html
This paper shows that the medication T3 inhibits AMPK in the hypothalamus, however it increases AMPK in muscles.

Inhibition by amino acids
Several reports have suggested a possible interplay between the mammalian target of rapamycin (mTOR) and AMPK signaling pathways coordinating amino acids- and energy-sensing. The mTOR pathway has recently emerged as a crucial point of convergence for signaling by amino acids, growth factors and cellular energy (Wullschleger et al., 2006). Whereas mTOR was presumed to be a direct cellular sensor for ATP levels, mounting evidence implicated AMPK in the regulation of mTOR activity. AMPK inhibits mTOR through direct phosphorylation of TSC2 tumor suppressor (Inoki et al., 2003) as well as critical mTOR-binding subunit raptor (Gwinn et al., 2008). Thus, mTOR activation and AMPK activity are inversely related (Aguilar et al., 2007). Recent studies demonstrated that AMPK activity is suppressed by amino acids (Gleason et al., 2007; Leclerc and Rutter, 2004). Treatment of C2C12 myoblast cells with leucine enhanced the phosphorylation of mTOR and concomitantly reduced the phosphorylation of AMPK and inhibited its activity (Du et al., 2007). The ability of leucine to dramatically reduce AMPK activity is linked to a consequent drop in the level of AMP and a subsequent decrease in AMP/ATP ratio. In the liver, the increase of protein intake induces metabolic adaptation characterized by concomitant increase of mTOR phosphorylation and decrease of AMPK phosphorylation (Chotechuang et al., 2009). Similarly, high protein diet decreases AMPK and increases mTOR activity in the hypothalamus, leading to reduction in food intake (Ropelle et al., 2008). Consistent with a cross-regulation between AMPK and mTOR to control food intake, hypothalamic ATP levels are increased and AMP/ATP ratio reduced after high protein feeding.

This paper shows the relationship between mTOR/AMPK especially in the presence of Leucine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132561/
 
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Murph

:)
Messages
1,799
@Murph Ketamine was nice. I enjoyed both some palliative relief of ME/CFS symptoms (pain and fatigue) but I also got some great mood boosting effects as well. Also music is enhanced on it. Are you considering a trial?

More info on mTOR/AMPK;

http://www.nature.com/nm/journal/v16/n9/full/nm.2207.html
This paper shows that the medication T3 inhibits AMPK in the hypothalamus, however it increases AMPK in muscles.



This paper shows the relationship between mTOR/AMPK especially in the presence of Leucine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132561/

I'm trying to stay out of the k-hole! ;)

I've also just found this paper which, (admittedly with a small sample size (10 subjects 7 controls) and in vitro) finds that ampk production is inhibited, not exaggerated, in me/cfs patients compared to controls.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982

so that throws a spanner in any ampk theory! My only comment is that the study looks to have very limited statistical power: It measured 3 time points after stimulation and found a significant difference at only one of them.
 

eljefe19

Senior Member
Messages
483
Ha I didn't experience the K hole no matter how high I pushed the dosing, which for me, I did pretty conservatively. Tried to keep it to 33-50mg bumps every few hours. @Murph

One thing I'm trying is a product called Myo-X on Amazon. It's advertised to increase circulating Follistatin and inhibit Myostatin, which should in turn disinhibit mTORC1. I'll report back on that.
 

nandixon

Senior Member
Messages
1,092
@nandixon What do you think about PEA? In summary, it inhibits AMPK in the hypothalamus, activates AMPK in fat tissue, from what I can tell disinhibits mTOR through disrupting the PERK-eIF2α pathway, and activates PPAR alpha and gamma.
The references I see indicate palmitoylethanolamide (PEA) should inhibit mTORC1 and therefore be bad.

I tried PEA a couple years ago (to inhibit microglia activation), and indeed it was very bad. I normally don't have significant brain fog but the PEA I took actually caused that. It was very insidious too. Probably one of the top 5 worst supplements I've ever taken.
 

eljefe19

Senior Member
Messages
483
The references I see indicate palmitoylethanolamide (PEA) should inhibit mTORC1 and therefore be bad.

I tried PEA a couple years ago (to inhibit microglia activation), and indeed it was very bad. I normally don't have significant brain fog but the PEA I took actually caused that. It was very insidious too. Probably one of the top 5 worst supplements I've ever taken.
Alright then, thanks, I'll hold off on that one.
@nandixon Are you still interested in BDNF? I have a new source of 7,8-DHF, also I found Magnesium L-Threonate which increases brain Mg levels, increasing BDNF and synaptic plasticity.
 

eljefe19

Senior Member
Messages
483
@nandixon @Murph So what if Chris Armstrong is right and ME/CFS mirrors starvation. Well, starvation is supposed to activate AMPK and inhibit mTOR. So, if our bodies' are stuck in starvation mode, and something like NAC can prevent the changes to AMPK and mTOR, perhaps that's why NAC has been shown in vivo to ameliorate ME/CFS symptoms. The authors of that study implied it was due to raised levels of GSH in the brain, but who knows?

Also Leucine directly inactivates AMPK.
 
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516
mTor and AMPK work in cycles over 24h with food and activity. It blunts mTor because the cells treat mTor as a major energy consumer (no matter the therapeutic effect you get from it). The best thing you get from AMPK is mitochondrial biogenesis. Thyroid is a major regulator, but AMPK and NO also synergize and trigger it in response to exercise (NO associates with both mTor and AMPK). The other major benefit is AMPK is a determinant of circadian rythm especially in skeletal cells. AMPK is probably a source of symptom relief from other supplements. The problem is activating it at inappropriate times (timing is everything) or too much with respect to mTor over 24h period, which you will very easily overdo. Sorry all I can write.
 
Messages
516
On Aminos, looks like Essential Amino Acids activate both mTOR and AMPK, but it appears that mTOR comes out on top? Not sure, but that would fit with people's anecdotal reports of Aminos being helpful.

https://www.ncbi.nlm.nih.gov/pubmed/27869123
I think this is intuitive if you feed amino acids alone. It mimics how protein feeding induces insulin and glucagon together, and the fact protein processing is not free. If you fed carbs with them I would expect AMPK to go down (well, I imagine you knew that).

Edit: It's fair to question [how much] that's exploitable for therapeutic purposes. For most people it wouldn't be worth it, but this is CFS/ME... I would frame it as: is it a net benefit or loss versus trying to amplify the mTor/AMPK cycle? In part depends on which downstream signals from AMPK survive. Too much to read. [Sorry for all the edits. This is why I shouldn't post on the internet on days like this.]
 
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eljefe19

Senior Member
Messages
483
I think this is intuitive if you feed amino acids alone. It mimics how protein feeding induces insulin and glucagon together, and the fact protein processing is not free. If you fed carbs with them I would expect AMPK to go down (well, I imagine you knew that).

Edit: It's fair to question [how much] that's exploitable for therapeutic purposes. For most people it wouldn't be worth it, but this is CFS/ME... I would frame it as: is it a net benefit or loss versus trying to amplify the mTor/AMPK cycle? In part depends on which downstream signals from AMPK survive. Too much to read. [Sorry for all the edits. This is why I shouldn't post on the internet on days like this.]
Lol no worries man I appreciate the post.
I appreciate any discussion on the topic, no matter how brainfogged.
 

eljefe19

Senior Member
Messages
483
@Tunguska Here's an idea for you bro. I highly recommend anyone interested in mTOR take a look at this;

There is a product on Amazon called Myo-X Myostatin Inhibitor. The company claims huge reductions in circulating Myostatin and similar increases in circulating Follistatin. Haven't been able to verify these claims yet. If you google 'MyoT12' you can find at least one study that claims it increases muscle hypertrophy, without specifics on the MOA. I'll find it and edit.

Have you been following the Activin B/Follistatin discussion? If the mechanism claims about MYO-X are true, this product could have massive benefit on mTOR signaling.

First of all, Myostatin inhibits Akt/mTOR (Reference). On top of that, Follistatin activates Akt/mTOR independently of Myostatin (Reference). So, in theory you would be getting a 2 + 2 = 5 benefit from this combination of actions.

I'm going to take my first dose tonight. I'll report back.
 

anne_likes_red

Senior Member
Messages
1,103
Don't want to derail but have to mention cold induced thermogenesis is supposed to inhibit myostatin via an increase in irisin.
As far as I know that's one way people - me included - have had an increase in muscle with cold exposure and no to little exercise.
Anne.
 

anne_likes_red

Senior Member
Messages
1,103
...Well 15 mins of shivering = the same amount of irisin as an hour of intense exercise. :ill: So not great options either way for pwME. :( Some people find wearing an ice vest tolerable.
Very slow, adaptive thermogenesis is possibly best. I did something like this - starting bathing a bit less than my skin temperature, and working down gradually. Enough shivering to stimulate adaptation, but not too much so as to crash. (Even with best intentions I still crashed in the early days.)
There was supposed to be an irisin drug in development but it wasn't successful. Probably best to stick with your original plan!